This application is for a planning grant to enable us to optimize the design of a clinical trial of ursodeoxycholic acid (UDCA) and methotrexate (MTX) in the treatment of patients with Primary Biliary Cirrhosis (PBC). PBC is a chronic cholestatic liver disease, predominantly of women, in which interlobular and septal bile ducts undergo inflammation and destruction. Once initiated, the disease persists and progresses at varying rates. Neither the initiating nor perpetuating mechanisms are well understood. Current concepts of pathogenesis include (1) destruction of bile ducts is maintained and perhaps initiated by autoimmune mechanisms; (2) hydrophobic bile acids which accumulate in serum and liver cause functional and cytotoxic liver injury; (3) cytokines and lymphokines released at sites of inflammation may contribute to cell damage and fibrosis. A considerable body of evidence indicates that UDCA when fed orally leads to improvement in liver tests, in pruritus and in liver histology, particularly in precirrhotic patients. It is too early to determine if survival or need for transplantation is affected. UDCA, a relatively non-toxic bile acid, when administered orally, alters the composition of the bile acid pool in favor of its enrichment with UDCA and appears to protect against the cytotoxic effects of endogenous bile acids that accumulate as a result of bile duct destruction. MTX is being shown to improve liver tests, symptoms and liver histology in a small number of precirrhotic patients with PBC. The mechanism of action is unknown but felt to be related to antiinflammatory-immunosuppressive effects of MTX. The current proposal will explore whether MTX improves the therapeutic effects of UDCA in precirrhotic PBC.